Chemotherapeutic salts



CHEMOTHERAPEUTIC SALTS Bernard Rudner and Albert Tockman, Baltimore,Md., assignors to W. R. Grace & Co., New York, N.Y., a corporation ofConnecticut No Drawing. Application March 4, 1957 Serial No. 643,541

11 Claims. c1. 260--239 .65)

is efiective for this purpose when administered orally.

Probably the most important of the acidic sulfonamides are the sulfadrugs, which are well known as chemotherapeutic agents. These compoundshave been applied with remarkable success as a cure for such bacterialdiseases as hemolytic streptococcal 'septicemia,streptococcalmeningitis, streptococcal peritonitis, streptococcal pneumonia,erysipelas, meningicoccal meningitis, pneumoniacoccal pneumonia andgonococcal infections. They have been less effective, but still useful,for ulcerative colitis, pneumonicoccal meningitis, staphylococcalsepticemia, gas gangrene, undulant fever, and chancroid. The best knownsulfa drugs are the derivatives of sulfanilamide o II Commerciallyavailable derivatives of this useful compound include sulfathiazole,sulfapyridine, sulfadiazine, sulfapyrazine, sulfaquinoxaline,sulfamethazine, sulfacetimide, sulfathalidine, sulfasuxidine, andsulfamerazene.

nited States Patent The commercially important sulfa drugs are. ofteneml ployed in aqueous media, frequently in the form of their alkalimetal or alkaline earth metal salts. This convenient and practicalmethod of administering these compounds is subject to unfortunatelimitations. It .is well known that sodium salts of some sulfadrugs,e.g.:ofsulfapyridine, are too alkaline in solution to be completelysatisfactory for injection, and too readily converted (even by thecarbon dioxide of the air) to the'more toxic free acid. Certain otherchemotherapeutic salts are too soluble in the physiological fluids topermit the building upof satisfactory anti-bacterial concentrations inthe body. We have found that new salts, having remarkable properties,are formed by replacing the alkali metal or alkaline earth metal ionwith a hydrazinium cation. Our new salts prior art limitations.

It is, therefore, an object of the present invention to provide a novelclass of quaternized salts of sulfonamide ICC or one of its derivatives,which are chemotherapeutically active. E

The present invention comprises combining, by metathetical reaction, ahydrazinium cation and a sulfonamide anion. The metathesis, which willbe discussed hereafter in further detail, is readily accomplished inanhydrous or aqueous solutions or by the fusion of two salts atrelatively low temperatures. The new salts produced by this method andcontemplated by the present invention comprise a hydrazinium cation ofthe surface active type and an anionic portion consisting of achemotherapeutically active sulfonamide derivative. The hydraziniumcation can be effectively supplied from the appropriate hydraziniumchloride. Such salts are thoroughly described in a co-pendingapplication S. N. 560,282, now abandoned, of B. Rudner, M. E. Brooks,and L. 0. Young, filed January 20, 1956.

Using the aforementioned metathesis technique we have discovered a novelclass of chemotherapeutic salts having a general formula:

[EMAI- R is acyclic residue having from 8 to 24 contiguous carbon atoms.Such a residue includes alkyl, alkenyl, alkadienyl, alkanoylamino,alkanoylaminoalkyl and alkanoyloxyalkyl groups.

R is a member of the group consisting of alkyl radicals having up to 24carbon atoms, alkenyl radicals having up to 24 carbon atoms, hydroxylower alkyl, hydroxy lower alkoxy lower alkyl, hydroxypoly lower alkoxylower alkyl, bis-hydroxyalkylaminoalkyl and carbon containing residueswhich when taken collectively with R represent the necessary atoms tocomplete an annular structure having from 5 to 6 endocyclic atoms. Rmaybe taken'collectively with R as indicated to complete a heterocycle.For example if R is CH CH O and R is CH CH oollectively they complete amorpholine structure. R individually is a member selected from the groupconsisting of alkyl radicals having up to 24 carbon atoms, alkenylradicals having up to 24 carbon atoms, hydroxy lower alkyl, hydroxylower alkoxy lower alkyl, hydroxy poly lower alkoxy lowerualkyl and bishydroxyalklyaminoalkyl.

A- in the above general formula is an anion derived from a benzenesulfonamide having the following structure: I f f R S-N-R R in thisstructure represents hydrogen, lower alkyl, amino, or a group which isreducible or hydrolyzable to amino. Groups hydrolyzable to amino includeacyl amino radicals, e.g. acetylamino, succinoylamino, butryrylamino andphthaloylamino; and aldehyde condensates, e.g. Schiif bases andaldehyde-bisulphite dehydration products. Groups reducible to amino areazo substituents, e.g. 2,4- diarninobenzeneazo, and hydrazo or hydrazinosubstituents. The negative charge of the benzenesulfonamido anion isgenerally on the N nitrogen. The N nitrogen is that atom adjacent to'thesulphur atom in the aforesaid structure. When R is an amino or acylaminogroup the nitrogen therein is usually difierentiated from thesulfonamidonitrogen (N by'the designation'N WhenR is an acylamino radical 'of adisbasic acid, e.g. succinoyl amino or phthaloylamino, the negativecharge of the anion is present on this group rather than the N nitrogen.R

is a member selected from the group consisting of hydrogen, carbamoyl,lower alkanoyl and pseudoaryl nitrogeneous heterocycles. Such anitrogeneous heterocycle is attached to the N nitrogen through'a carbonatom-Which is doubly bonded to a heterocyclic nitrogen. The'term'pseudoaryl *nitrogcneous heterocycles embraces a: group it isespecially appropriate that the possible variations of both anion andcation contemplated by our invention be 'throughly understood at thispoint.

First, with respect to the cationic structurepitis essential that thehydrazinium cation be of the surfaceactive type. In general, the surfaceactivetype of hydrazinium salt comprises a molecule made up of ahydrophobic group such as derived from long chain alkyls (.e.g. a carbonchain of 824 contiguous carbon atoms) and a water solublizing orhydrophilic group. The presence of such 'a'cation in solution hasthe'effectof lowering the interfacial tension at interfaces withinthe'solution. Thus, when a solution of one of our novel salts iscontacted with bacteria the surface tension at the liquid-solidinterface is considerably reduced thereby permitting the solutioncontaining the germ-killing sulfa drug to'spread over and thoroughly wetthe surface of the bacteria. Of even greater significance aretheinherent antiseptic and penetrating properties of the hydraziniumcation. The-ease of penetration of the bacterial cell generally reducesthe relative concentration 'of chemotherapeutic salt necessary to killbacteria. Furthermore, thesurfactant hydrazinium cation tends to reducethe toxicity of the sulfonamide derivative, thereby making theseimportant compounds available for applications where a mitigationof-the-tox- 'icity is a basic requirement. Specific but non-limiting examplesof suitable hydrazinium salts containing cations within the abovedescribed generic group are shown hereunder in Table I by name andformula.

TABLE I Methyldihydrotallowhydrazinium chloride CIO-IBHSB-U CHrN-NH: C1

lia-16 w Dimethylsoyahydrazinium chloride OH; 1e1s a1a7 -N 2 C1 1,1dimethyl 1 [2 (4 octylphenoxyethoxy) ethyl]- 'hydrazinium chloride 1,1bis (2 hydroxyethyl) 1 [3 (N B hydroxyethyl) N octadecyl aminopropyl 1-.]hydrazinium chloride B00111; CzH OH N-;H,N- I 01 'HOCzHr NH: CISHMDimethyloctadecylhydrazinium chloride 50H; OISH I v-NH, o1-

1,1 bis (hydroxytetraethoxyethyl) l octadecylhydrazinium chloride 1,1bis (hydroxytetracosethoxyethyl) 1 octadecylhydrazinium chloride FT 0rem ss-E NHQ 1,1-dimethyl-leheitadecylhydrazinium chloride1-coco-1,1=dimethylhydrazinium chloride'l,l-dimethyl-l-dodecylhydrazinium chloride 11,1dimethy1-1-(2-lauroyloxypropyl) hydrazinium acetate 7 o n omc im-omrtonsf [011300,]

"1,1,l,-tris- (-p stearoyloxyethyl) hydrazinium chloride 1 bis (2hydroxyethyl) 1 (2 oleoylaminoethyl) 'hydrazinium sulfate C 2H4 O H1-amino-1-( Z-hydrox-yoctadecyl) piperidinium-chloride v1 -rethyl 1 ([3hydroxypropyl) 1 (3 oleoylaniinopropyl) hydrazinium chloride Cz s. *5

' oflnuoNnonlomonzNornonorr or H, CH

l-carboethoxymethyl-l,l-dicetylhydrazinium chloride NH: 0 (cm aah HaH! 001 51 1,1 bis 2 hydroxyethyl) 1 2 -,palmitoylaminoethyl)hydraziniumchloride 1 (1 carbobutoxy 8 hydroxyoctadecyl 9) 1,1 dimethylhydrazim'umchloride Benzenesulfonamide Benzenesulfonylurea twins1-(p-ethylbenzenesulfonyl)-3-butylurea N -acetylsulfanilamide I CH C0NHCH SO NH Sulfacetimide Prontosil HiNQ N=NmH4soiNHi Sulfapyrazine H D- a o4SOiN-O Sulfaquinoxaline Sulfamethazine C H; P-HgNCgEhS OQN- p-HgN C @118 0 3N' Diphthaloylsulfanilamide I r O i 041020 GHQONHQiNH 015E441 011-02- (4-benzylideneaminobenzenesulfonyl) aminopyn'dine Nacetylsulfathiazole v 1 ii II /N l A I s- H Sulfamerazine The N; oramino nitrogen has attached to it hydrogen atoms, or any group which byreduction or hydrolysis is converted to hydrogen atoms. This isespecially important, for if the amino nitrogen is substituted with agroup that cannot be removed in the body the activity is entirely lost.1

= We have already indicated that our novel chemotherapeutic salts aremade by metatheticall reaction. Tables I and II are specific indicia ofsuitable parent salts which may be selected for use in the formulationof our novel compounds. Generally speaking, the hydrazinium halides arethe most readily available to supply the necessary surfactanthydrazim'um cation. The hydrazinium chlorides may be prepared byreacting chloramine with the appropriate tertiary amine; chloramine, ofcourse, may be economically obtained in commercial quantities using thewell known process of Harry H. Sisler et al., described in US. PatentNo. 2,710,248, where chlorine and 7 ammonia are reacted in a vapor phaseto produce 'chloramine. Table I, supra, indicates that the appropriatehydrazinium acetate\or sulfate is also suitable. In fact, other saltssuch -as the iodide, nitrate, phosphate, carbonate, borate, benzoate,etc., can also be used if one wishes to modify the simpler reactionprocedure. The sulfonamide derivative may be the free baseritselfinrzanalkali or alkaline earth metal salt from the free base.

Our novel chemotherapeutic salts can be made in anhydrous or aqueoussolution. 'The selection of reaction medium depends primarily on thesolubility .of the prodnot. If the product is water-insoluble,=we havefound it convenient to prepare aqueous solutions of the parenthydrazinium salt and the parent sulfonamide derivative. When two suchsolutions are mixed the desired product readily precipitatesout and canbe easily separated by filtration. If, however, the product salt isWater-soluble both the hydrazinium salt and the sulfonamide derivativecan be dissolved'in an unreactive organic solvent before adding themtogether. The term unreactive used to describe the solvent means suchsolvents which do not react preferentially with the product or .thereactants. Solvents suitable for this purpose include "such "neutralliquids as hydrocarbons (e.g. hexane, cyclohexane and xylene); alcohols(e.g. methyl, ethyl, isopropyl, butyl, 2- ethoxy-et-hyl, and ethyleneglycol); ethers (e.g. diethyl ether, dioxane, .tetrahydrofuran and'tet-rahydropyran; esters (e.g. ethyl acetate and triethyl phosphate);amides (e.g. dimethylformamide); nitriles (e.g. acetonitrile andbenzonitrile); nitro compounds (e.g. 2-nitropropane and nitrobenzene);ketones (acetone, methyl isobutyl ketone and acetophenone); and'halocompounds (chloroform, and bromobenzene). In general, use of a polar,watermiscible solvent, or Water itself is advantageous. When anhydrousmedia are used the inorganic :-salt zimpurity precipitates from thereaction mixture and may be filtered off. The desired chemotherapeuticsalt can then be separated from the filtrate by conventional laboratoryprocedures.

As an alternative procedure it is-possible to fuse .at low temperaturestwo anhydrous salts and then extract the product or impurities.Throughout the application we will refer to the hydrazinium chlorideaandtthepsodium salt of the sulfonamide compound as intermediates. This isdone simply for the purposes of illustration since these are themost-readily available parent "salts. Obviously the same organicproducts may be prepared using other salts as shown below in Equations 1and 2.

The advantages resulting from'th-e synergisticcombination of thesurfactant hydrazinium cationwit'h'a'sulfonamide compound also obtainwith-compounds comprising the cation of a surfactant hydrazinium-saltand the the bodily fluids. Salts of this type show advantage over thecommercially useful amine salts of Penicillin G (e.g. thedibenzylethylenediamine salt). Replacement of the antibiotic moiety byother pharmaceutical residues, e.g. barbiturates, aspirin, and phenols,,gives 1 products .with similar advantages.

Our invention is "further illustrated by the following examples.

EXAMPLE I 50 g. of USP sodium sulfathiazole and 8 g. of sodium hydroxidewere dissolved in 750 ml. of water. This solution was treated with 2'5g. -of dimethyloctadecylhydraziniurn .chloride. The hydrazinium saltfloated on top. The reaction mixture was carefully .layered with 100 ml.of acetone and then stirred rapidly for 30 minutes, thereby convertingthe two liquids to a liquid and a solid. The mixture was filteredand thesolid obtained therefrom was washed with limited uantities .of cold.water. It was dried to yield 40 -g. 'of .a white powder which formedsoapy emulsions .in water. The powder was recrystallized 3 times fromethyl acetatetogiveZZ g. of glistening white plates; the novelchemotherapeutic salt, 1,1-dimethyl-l-octadecylhydrazinium salt of.sulfathiazole:

This new product shows a transition point and melts under pressure at 83C. It is recrystallizable from water and soluble in chloroform and ethylalcohol.

EXAMPLE II The procedure of Examplel was substantially repeated using 50g. of sulfapyridine, 15 g. of sodium hydroxide in 750 ml. of water and25 g. of dirnethyloctadecylhydrazinium chloride. Recrystallization ofthe ultimate product gave very glossy .mattedplatesrwhich-melted=at-82C. having properties similar to those of the sulfathiazole saltdescribed in Example I. The-structural formula of the novel product thusobtained is shown hereunder.

EXAMPLE III Using a procedure similar to that. described in thepreceding examples, '85 g. of sulfapyridine and 30 g. of sodiumhydroxide dissolved in 750 ml. of water were treated with '45 g. .of.methyldihydrotallowhydrazinium chloride. The solid product obtainedfrom this.reaction mixture was recrystallized twice from ethyl acetateto give 32. g. of a microcrystalline white powder that melted at 82 C.This new product was less soluble in cold water but more soluble inchloroform and dimethylketone than either the product of Example I orII. Its structural formula is shown below.

o OH=OH The tertiary amine .used to prepare the parent hydraziniumchloride is claimed-by its-.manufacturers to be a mixture containingapproximately tertiary amine, of which approximately 70% ismethyldioctadecylamine,

and 37% octadecadienyl on aweight percent basis. white powder obtainedas a product represents a more f 9 23% methyldihexadecylamine, Itrioctadecylamine, and 2% tris-hexadecylamine. 1

. EXAMPLEIV A 60 'g. portion of sulfadiaz'ine and 30 g. of sodiumhydroxide were added to'7-50 ml. ofwater. This solution was tr eatedwith 35 g. of methyldihydrot'allowhydrazinium chloride. The hydraziniumchloride was slurried in 150 ml. of hot dimethylketone and rapidly addedto the sulfa solutionzwith vigorous-stirring. The solution was filtered;and the solid obtained therefrom was recrystallized with hexane to give17 g. of an amorphous white powder." The novel product was even morewaxy than that of Example III. It showed a phase change at about 65 C.and melted clear at 100 C.

EXAMPLE V 40 g. of soydimethylhydrazinium chloride (a brown gumcontaining about 55% ammonium chloride) were slurried in 200 ml. of hotdimethylketone. This mixture was added rapidly with good stirring to 55g. of sulfadiazine and 30 g. of sodium hydroxide'dissolved in 750 ml. ofwater. The resulting solution was allowed to stand overnight to give ared oil with a density less than one. The mixturewas frozen and thewater was decanted therefrom. The oily product was resuspended in 200ml. of water and extracted three times with equal volumes of chloroform.Chloroform extracts were dried over magncsium sulfate and added to anequal'volume of CqHm. A red oil precipitated from the mixture and thesolvents were-decantedtherefrom. The oil was evaporated to dryness togive a red .gel. The gel was precipitated several times from ethylacetate bytreatment with n-heptane to give a gummy brown powder. Thismaterial was vacuum dried to give an off-white powder melting at about86 C.

The parent soy amine from which the hydrazinium salt was made is claimedby its manufacturer to be a mixture of dimethylalkylamines in whichalkyl is approximately 20% hexadecyl, 17% octadecyl, 26% octadecenyl,The

nearly saturated fraction than the dark brown oil ob.- tained onevaporationjofthe purification mother liquors.

EXAMPLE vi 60g. of 1;l=bis (hydroxysesquihexoxyethyl)-1-soyhydrazinium'chlor'ide in'200 '-ml. of dime't-hylketone were added to 105- g. ofsulfa'sux-idin'e in750 ml. of water and It is obvious that the aboveformula represents an average of the hydrazinium substituents since thesoy portion contains a mixture of alkyl radicals indicated in Example V.The novel product softens at about 60 C. and melts at about 225 C. Itundergoes partial decomposition at about 200 C. It is highlywater-soluble and insoluble in-ichloroform and ethylacetate.

- lsxnlvrrlllavllv I 3 A 5 g. portion'of 'the'product of Example VI wasdissolved in 100' mlfof water and cautiously acidified with glacialacetic acid. The resulting mixture was cooled, filtered, dried andrecrystallized to give a good yield of 10 an amorphous white powderhaving one of the possible structures shown below:

110,0 mmo-NQsmN-o This novel compound shows a transition temperature atabout 110 C. and melts at about 143145 C. It is soluble in ethylalcohol.

EXALLPLE VIII Using a procedure substantially similar to that describedin Example V, an aqueous solution containing 25 g. of sulfanilamide and20 g. of sodium hydroxide was treated with 25 g. of1,1-dimethyl-1-[2(4-octylphenoxyethoxy) ethyllhydrazinium chlorideslurried in hot dimethyl ketone. The mixture on standing overnightformed a red oil. It was chilled and the aqueous layer decantedtherefrom. The red oil was dissolved in 200 ml. of water and clarifiedby decantation. It was added to an equal volume of dimethyl ketone toreprecipitate the oil. The resulting mixture was saturated with solidpotassium carbonate, chilled, and the lower colorless aqueous layer wasdecanted therefrom. Evaporation of the dimethyl ketone layer (the upperred layer) gave 28 g. of a viscous red oil which was vacuum dried to avery viscous foaming red oil. The novel oil was readily water-soluble.Treatment with chloroform gave very fine silken needles which began tomelt at about 60 C. and melted clear at 161-162 C. This novelchemotherapeutic salt has the formula:

and melted clear under pressure at about 68 C. Its

formula is shown below:

0 I CH3 [C HaalilNCHgCHgCHDBCHg] I [Hm-@- lei NC o In] Emma x g. ofsulfaquinoxaline and 35 g. of sodium hydroxide' were dissolved in 1000ml. of water. "This solution was treated with -40 g. of-methyldicocohydrazinium chloride in 100 ml. of acetone to give a thickslurry. The slurry was chilled. and the :water was decanted therefrom.The residual oil was dissolved in ethyl acetate and reprecipitated byaddition of 2 volumes of n-hexane. The resultant oil, in acetone, gave,after clarification and evaporation, a dark varnish. This material wasdissolved in chloroformand precipitated with diethyl ether to give ayellow oil. This material was dried under 3 mm. vacuum at 35 C. to givea gum which softened at about 50 C. (melting underpressure) and ranclear at about 103 C. The parent hydrazinium chloride has the generalformula:

In the above formula R, being derived from coconut oil fatty acid, isaccording to its manufacturer a mixture of approximately 8% octyl, 9%decyl, 47% dodecyl, 8% hexadecyl, octadecyl, 18% tetradecyl and 5%octadecenyl on a weight percent basis. The novel sulfaquinoxaline saltwas less soluble in water than any of the products of the precedingexamples.

EXAMPLE XI The procedure of Example I was substantially repeated to givethe sulfamerazine salt of methyldihydrotallowhydrazinium cation; a drywhite powder softening at about 65 C. and melting at about 75 C.

EXAMPLE XII white prisms melting atabout 106 C. The novel salthas theformula:

It is recrystallizable from, and forms gels in water. It is soluble inethanol and acetone.

EXAMPLE XIII Similar treatment of l-p-tolysulfonylurea and I-amino-1&2hydroxyethyl)-2-heptadecenylimidazolinium nitrate gave an oxidizedmixture from which the novel chemotherapeutic salt could be tediouslyisolated. Using these same parent salts and substantially repeating theprocedure of Example I gave, after recrystallization from an ethylacetate-isopropyl alcohol mixture, a better yield of off-whitemicrocrystalline product having the formula:

This novel salt softened at about 68 and melted clear at about 131 C.

EXAMPLE XIV Equal portions (0.01 moles) of 1,1-bis-(2-hydroxyeth-1yl)-l:[3 (N-fl-hydroxyethyl N- octadecyl)aminopropyl- 12 l-lhydraziniumchloride and N -acetylsulfanilamide were refluxed in ml. of isopropylalcohol for 3 hours. The resulting mixture was evaporated dry on a steambath and extracted with chloroform. Recrystallization from an ethylacetate-benzene mixture gave thick tan noncrystalliz ng product havingthe structural formula:

EXAMPLE XV Ahydrazinium chloride made by the chloramination ofcommercial amine known as .Ethomeen S/60.-is.a product of the averageformula:

[ iavn za-av fl(021 4 12 121 .A 5% aqueous solution of this hydraziniumsalt was treated with an excess of a 54% by weight aqueous solu- .tionof commercially available sodium sulfathiazole, .U.S.P. XIV grade. Thereaction mixture becameslowly turbid and after 24 hours nearlyquantitative precipitate .was obtained therefrom. This material wasrecrystallized from water'to give brilliant flat platesmeltin-g underpres sure at about 142 C.

EXAMPLE XVI A series of semi-micro tests were carried out to de terminethe nature of the products on-a comparative basis using a variety ofsulfonamido compounds and by drazinium chlorides. The procedure forthese tests was as follows: 5% aqueous solutions of the sodium salts of(1) sulfanilamide (2) sulfathalidine (3) sulfanilylurea and (4)sulfamethazine'were prepared using 1.2 equiv alents of sodium hydroxideto 1 equivalent ofsulfa com pound. 5% or saturated aqueous solutions of4 hydrazin-ium chlorides having the average structuralformula shownhereunder were prepared.

The sixteen experiments are summarized in Table III. Equal volumes ofeach'solution were mixed together (the reaction mixture containingexcess sulfa) and allowed to sit for 24 hours. After that time themixtures were cautiously acidified with acetic acid. The initial resultand the result .on acidification aresho'wn .T able III.

TABLE, III; ,S'ulfonamidecompound Hydrazinium Salt i "-2 y a 4 A "Slow.gel going 1100- No ppt;gelwith acid. Slow ppt; more ppt. Quick ppt; nochange culent; 'no change I with acid. with acid. l withacidy v v Noppt; slow tnr- Slowturbiditmppt. Slow ppt;moreppt. Slow crystalformabidity with acid. with acid. with acid. tion; no change. No ppt; nochange" Slow turbidity; no Slow ppt; no change. Slow crystal formaj lchange. tion; no change. D No ppt; no ppt No p t it; sglta pptd N ppt;nppt N0 mph; 110 ppt.

ppt. precipitate. EXAMPLE XVII A commercially available pharmacenticallyapproved solid mixture containing equalweights of vsl'llfacetimide,sulfadiazine, and sulfamerazine was dissolved in 20 times its totalweight of water by the careful addition of dilute sodium hydroxide. Thissolution was treated with one equivalent (to three of sulfa drugs) of1,1-bis-(2- hydroxyethyD-l-[3(N-fi-hydrox'yethyl-N-octadecyD-aminopropyl-l-lhydrazinium chloride as a10% aqueous solu tion. The mixture was evaporated to dryness in, an airstream and extracted with isopropyl alcohol. An offwhite product wasobtained ,on evaporationof the solvent. It was a mixture of sodiumand-hydrazinium salts which, unlike the starting sulfa compounds,wasdispersible in both water and peanut oil. The experiment Was repeatedusing three times as much hydrazinium salt. The sodium content of theisopropyl alcohol soluble product was reduced to almost ,zero. Theproduct obtained on evaporation of the solvent was soluble in Water,chloroform and peanut oil. V i I f Our novel products are'exceedinglyvaluable, in the formationof self-sterilizing, water andsolvent soluble to dispersible medications. Eurthermore, the synergisticcombinations of surfactant hydrazinium cation and sulfonamido anion havethe following remarkable properties. First, wetting, spreading, andpenetrating ability. These attributes of, our novel chemotherapeuticsalts facilitate more effective inhibition or destruction. Second,anti-oxidant action. The surfactant hydrazinium cation is an effectiveanti-oxidant which protects the readily oxidizable sulfonamido portionof our novel salts. Third, dispersibility in both oil and water. Thisproperty insures effective contact with bacteria in both types koniumchloride). They are also comparable or superior to phenol in theirbacteriostatic and fungistatic'activity. Tables IV, V and VI.presentcogent evidence of the eifectiveness of ournovel'salts.Qctadecyldimethylhy drazinium sulfathia'zole was chosen asrepresentative of our novel salts. Zephiran and phenol are common standards in bacteriostatic and fungistatic tests.

Table IV shows the bacteriostatic activity of one of our typicalchemotherapeutic salts in comparison to Zephiran. Table V shows thebacteriostatic activity of the same salt when compared to phenol. TableVI shows fungistatic activity using, phenol as a standard. The tablesshow inhibition of growth expressed in millimeters of representativebacteria and fungi by 0.1%, 0.01%, and 1% weight/volume neutral (pH 7)aqueous solutions of the chemotherapeutic salt. Zephiran and phenol,each at 0.01%, 0.1% and 1% weight/volume aqueous concentrations areshown as controls. The bacteria were routinely tested on nutrient agaror nutrient gelatin. The fungi were routinely tested on eitherSabourauds dextrose .aganor potato agar. Each test was performed induplicategon two diiferent days. The averageamount of inhibition, basedon four individual measurements is presented. Inthe tables a small pnext to the'inhibition' measurement indicates partial inhibition,Because of the nature ofthe Oxford cup technique, the results showingeither complete or partialinhibition areroughly'comparable.

TABLE IV Bacteriostatic activity [Octadecyldimethylhydraziniumsulfathizaole salt (1) v. Zephiran (2)] of solution; a result which doesnot commonly obtain Bactera using H O soluble bacteriocides. Fourth,self-sterilizaconcentration of 1 tion, a desirable property notpossessed by the parent Test Materials Medium P t P d S tchemotherapeutic sulfa drugs. Fifth, dmnmshed alkalmmen a ei itg izt ofimir ie cir is fzi zi t o it i'ie ity. The sodium salts of some of theparent sulfa drugs (1) (2) (1) (2) (1) (2) are too alkaline in solutionand hence unsatisfactory for injection. Sixth, stability. Our novelcompounds are 14 not readily converted to the more toxic free acid. 16p-lO 20 p-13 18 p17 The parent sulfa compounds show little in vitroactiv- 638 22 ity. However, our novel chemotherapeutic salts are sur-0.1 .do 1910 prising from t 18 standpoint. In a series of 1n v1tro testsL0 Nutrient 26 12 they showed excellent bacteriostatic properties whencompared to the commercial drug Zephiran (refined benzalp=partia1mhibmmTABLE V Bacteriostatic activity [0ctadecyldimethylhydraziniumsnlfathlazole salt (1) v. Phenol (2)] Bacteria Concentration of Test Ma-Medium terial, Percent Micrococcus Serratia Pseudomanas K'lebsiellcpyopencs marsecens aeruginosa pneumoniae V81. aureus Nutrient agar- 12p10 14 11-10 10-10 1) 1010 do 14 p-10 20 p-10 do 1a p-15 25 p-28Nutrient "Plath fin fln p-partial inhibition.

F n Concentration of Test Material, Percent Medium Candida C'haetomiumAlbicans Globosum 0.01 Sabourauds--- 10-410 1 dextr 10 1 0 agar 1023 p-,9:- ==T.-=:==:==: 0 1 agar 105 1 n 12-58 We claim;

1. As a new chemical compound, the 1,1-dimethy1-loctadecylhydraziniumsalt of sulfathiazole.

2. As a new chemical compound, the '1,1-dimethyl-l-('3-stearoylaminopropyl) hydrazinium salt of sulfacetimide.

3, As a new chemical compound, the 4-amino-4-cocomorpholinium salt ofsulfanilamide.

4. As a new chemical compound the 1,1-bis(hydroxyethyl)-'l-soyhydrazinium salt of petoluenesulfonylurea.

5. As a new chemical 'compoundthe 1,1-bis-(hydroxysesquihexoxyethyl)-1-soyhydrazinium salt of sulfasoxidine.

6. New chemotherapeutic salts having the foil-owing structure:

wherein R is a member selected from the group consisting of acyclicalkyl and alkenyl hydrocarbon radicals having 8 to 24 carbon atoms,acyclic alkylcarbonylaminoloweralkyl radicals containing a total of from8 to 24 carbon atoms, acyclic alkylcarbonyloxyloweralkyl radicalscontaining a total of from 8 to 24 carbon atoms and acyclicalkylcarbonyloxylowcralkylaminoloweralkyl radicals containing a total offrom 8 to 24 carbon atoms;

R and R .taken separately are members selected from the gronpconsisting.ofacyclic alkyl and alkenyl hydrocarbon radicals containing 1.to 2 carbon atoms, hydroxyloweralkyl andhydroxypolyloweralkQXYIQWeralkyl;

3 and ll rtaken together with the N on which t ey are both substituentsform a ring system selected from the group consisting of morpholine,piperidine and pyrrolidine; Y is a member selected from the groupconsisting of hydrogen, lower alkyl, amino, lower alkylcarbonylamine,succinoyl, benz alkylideneimine, benzeneazo, benzenehydrazo andbenzenehydrazino; .Z is a member selected from the group consisting ofhydrogen, carbamoyl, lower alkanoyl, oxazole, isoxazole, thiazole,pyridine, pyrimidine, pyrazine, quinoline, quinoxaline,loweralkyloxagolc, loweralkylisoxazole, .loweralkylthiazole,loweralkylpyridine, loweralkylpyrimidine, loweralkylpyrazine,loweralkylquinoline and loweralkylquinoxaline.

7. Compounds according to claim 6 wherein R is an acyclic alkylhydrocarbon radical having 8 to 24 carbon atoms, R and R are acyclicalkyl hydrocarbon radicals containing 1 to 25 carbon atoms, Y is aminoand Z is thiazole.

8, Compounds according to claim 6 wherein R is an acyclicalkylcarbonylaminoloweralkyl radical, R and R are acyclic alkylhydrocarbon radicals containing 1 to 25 carbon atoms, Y is amino and 'Zis lower alkanoyl.

9. Compounds according to claim 6 wherein R is an acyclic alkylhydrocarbon radical having 8 to 24 carbon atoms, R and R together withthe N on which they are both substituents form the morpholiue ring, Y isamino and Z is hydrogen.

10, Compounds according to claim 6 wherein R is an acyclic alkenylhydrocarbon radical having 8 to 24 carbon atoms, R and R arehydroxyloweralkyl, 'Y is lower alkyl and Z is carbamoyl.

11. Compounds according to claim 6 wherein R is an acyclic alkenylhydrocarbon radical having 8 to 24 carbon atoms, R and R arehydroxypolyloweralkoxyloweralkyl, Yis succinoyl and Z is thiazole.

No references cited.

1. AS A NEW CHEMICAL COMPOUND THE 1, 1 -DIMETHYL-1OCTADECYLHYDRAZINIUM SALT OF SULFATHIAZOLE
 6. NEW CHEMOTHERAPEUTIC SALTS HAVING THE FOLLOWING STRUCTURE 